1. Field of the Disclosure
The present disclosure relates to improved materials including hyperpolarized nuclei and techniques for making the same.
2. Description of Related Art
Recent experiments have demonstrated that hyperpolarization of various nuclei can survive the transition from one molecule to another that takes place during a chemical reaction. For example, it has been shown that hyperpolarized (“HP”) 13C nuclei in sodium pyruvate can be metabolized by cancerous tissue and produce HP lactate, alanine and the like.
A further example can be found in the production of HP fumarate, which can be manufactured by first hyperpolarizing nuclei in fumaric acid and then allowing the acid to react with a base solution to form HP fumarate. HP sodium pyruvate (i.e., sodium pyruvate including hyperpolarized nuclei) may be manufactured in a similar fashion. In reactions such as these the amount of polarization lost during the chemical reaction has been shown to be small.
These are examples of chemical reactions in which at least one precursor molecule in the chemical reaction is hyperpolarized so that at least one of the end products of the chemical reaction is in turn hyperpolarized.
In each of the aforementioned examples, Dynamic Nuclear Polarization (DNP) was used to hyperpolarize the precursor molecule. In this process, the molecule to be hyperpolarized is mixed with a polarization agent containing a source of free electrons, typically a trityl radical (TA). In some instances an electron paramagnetic agent (EPA) may be used in conjunction with the TA or by itself.
This method of hyperpolarization is problematic for in vivo applications, as the TA/EPA is strongly contraindicated for in vivo applications. The TA/EPA must then be stringently removed prior to injection of the HP material. However, the level of polarization in the HP material that survives after filtration of the TA/EPA is not presently clear. Moreover, safe levels of exposure to small amounts of TA/EPA have not been established by the FDA. Furthermore, use of this technique is not amenable to the ready transport or storage of hyperpolarized material.
Very high nuclear polarizations can be produced in materials containing nuclei with non zero spin using a variety of methods well known in the art. The simplest of these is to subject the material to very high magnetic fields (typically, B>10 T) and very low temperatures (typically, T<100 mK) where the saturated nuclear polarization of any non zero spin nuclei is very high.
Unfortunately, under such conditions, the relaxation time of most nuclei is extremely long because at low temperatures, molecular motion, which is a major source of nuclear magnetic relaxation, is greatly diminished. To address this drawback, a variety of relaxation agents have been used to reduce T1 in the high B/T environment including dysposium, gadolinium, oxygen and others.
An alternative to employing a relaxation agent is to incorporate a polarization agent such as a trityl radical and then transfer polarization from the agent to nuclei in the target material. This approach has the advantage of not requiring such low temperatures or high fields and has been used to demonstrably produce very large polarizations in small amounts of material. It has become the basis of a commercially available research device with the trade name Hypersense®.
However, admixture of either an external relaxation agent or a polarization agent has a number of drawbacks. First off, they are generally equally effective at depolarizing the material while still in the solid state upon removal from the high B/T environment. This makes it very difficult to store/transport the hyperpolarized material any significant distance from the polarizer and therefore mandates that the polarizer be placed very close to the MR machine in which the study utilizing hyperpolarized material is to be carried out. Secondly, most relaxation or polarizations agents are frequently toxic. This makes such agents problematic for use in in vivo MR studies.
For this reason alternative relaxation agents that are non toxic and can furthermore be removed without depolarizing the material have been developed. For example, U.S. Pat. No. 6,651,459 teaches the use of 3He as a relaxation agent by adsorbing layers of 3He on a high surface area substrate constructed from the material to be hyperpolarized. Quantum tunneling in the 3He overlayers causes rapid relaxation in the underlying material leading to rapid saturation of the nuclear polarization in a high B/T environment. 3He is chemically inert and can moreover be thoroughly removed from the material prior to warm up from a high B/T environment which addresses in vivo usage concerns. U.S. Pat. No. 6,651,459 further teaches the use of 4He to remove the 3He from the surface of the polarized material to minimize depolarization upon warmup.
An aspect of the above process is that the 3He can only effectively relax the substrate layer with which it is in intimate contact. Thus, the material must be made into a very high surface area substrate prior to polarization which may impose material handling difficulties.
There is therefore a need in the art for a methods of manufacturing hyperpolarized (“HP”) material where the material is not mixed with any kind of external relaxation or polarization agent. More generally, there remains a need in the art for improved approaches to manufacture, transport and use of highly polarized materials. The present disclosure provides a solution for these problems.